Flosequinan is one of a class of quinoline compounds having therapeautic potential as antihypertensive agents or in the treatment of heart failure. Recently, flosequinan has been found potentially useful in the treatment of erectile dysfunction, as disclosed in commonly owned U.S. Pat. No. 6,110,489 and patent application Ser. No. 09/166,703, the contents of which are incorporated by reference herein.
The synthesis of flosequinan has been discussed in the literature and has been the subject of several patents. In Birch et al., Synthesis of Flosequinan: A Novel 4-Quinolone shown to be useful in Congestive Heart Failure, J. Chem. Soc. Perkins Trans. 1994, 387-392, the authors describe two approaches to the synthesis of flosequinan and its metabolite, flosequinoxan. The first approach was used in part by the inventors in developing the novel pathway disclosed herein. However, there are several significant differences and improvements in the novel pathway disclosed by the inventors herein, which result in high yields and purity as compared to the prior art.
Some of the authors of the above literature reference are named as inventors on several patents, including U.S. Pat. Nos. 5,011,931 and 5,079,264 and European Patent No. 0135367. These three patents include various synthetic steps that have been used historically in the synthesis of flosequinan. These patents do not, however, disclose or suggest the inventive pathway described by the inventors herein.
Other literature references relating to the synthesis and characterization of flosequinan include Kashiyama et. al., Stereoselective S-Oxidation of Flosequinan Sulfide By Rat Hepatic Flavin-Containing Monooxygenase 1A1 Expressed in Yeast, Biochemical Pharmacology, Vol. 47, No. 8, 1357-1363 (1994); Russell et. al., The Synthesis of 2,3-Ring-Fused Analognues of 7-Flouro-1-methyl-3-(methylsulfinyl)-4(1H)-quinoline, Synthesis, 753-755 (August 1992), and Morita et. al., Synthesis and Absolute Configuration of the Enantiomers of 7-Flouro-1-methyl-3-(methylsulfinyl)-4(1H)-quinoline (Flosequinan), Chem. Pharm. Bull. 42(10), 2157-2160 (1994). The last of these references addresses synthesis of optically active flosequinan via diastereomeric separation of certain (R)-methylbenzylamine derivatives and the determination of their absolute configuration by X-ray crystallographic analysis.